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Bradykinin analogs as selective inhibitors of cell activation

a thrombin-induced cell and analog technology, applied in the direction of peptide/protein ingredients, extracellular fluid disorder, peptide sources, etc., can solve the problems of affecting the safety of patients, high reocclusion rate, and high complication rate, and achieve the effect of inhibiting thrombin-induced platelet and preventing platelet aggregation

Inactive Publication Date: 2006-01-03
MICHIGAN UNIV OF THE RGT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0034]The invention also comprises the use of a compound according to formula I, II, or III for the preparation of...

Problems solved by technology

However, after intracoronary thrombolysis with lytic agents, the reocclusion rate is high.
This expected high complication rate frequently requires an additional operation with attendant complications.
The tradeoff for effective anticoagulation, however, was increased hemorrhage into brain leading to the termination of three clinical trials.
These non-selective inhibitors of α-thrombin have an antithrombotic efficiency dose close to their toxicity dose and are not clinically tolerated and, thus, may never have commercial significance.

Method used

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  • Bradykinin analogs as selective inhibitors of cell activation
  • Bradykinin analogs as selective inhibitors of cell activation
  • Bradykinin analogs as selective inhibitors of cell activation

Examples

Experimental program
Comparison scheme
Effect test

example 1

In Vitro Functional Assays

[0101]Functional assays are used to evaluate the relative inhibitory efficacies of the methods and compounds according to the invention. In these assays, native BK (SEQ ID NO:5), the BK fragment Arg-Pro-Pro-Gly-Phe (SEQ ID NO:7), or another BK analog, may be used as a positive control peptide.

A. Inhibition of Platelet Aggregation

[0102]For human platelet aggregation studies, 50 ml human blood was collected into a syringe containing 5 ml of 0.013 M sodium citrate. The anticoagulated blood was centrifuged at 180 xg for 10 minutes at room temperature and the platelet-rich plasma was the supernatant. Platelet aggregation studies in platelet-rich plasma were performed in the cuvette of an aggregometer using γ-thrombin (Haematologic Technologies, Essex Junction, Vt.). After standardization of the aggregometer, the threshold dose of γ-thrombin, defined as the minimal concentration that will induce full platelet aggregation, was ascertained for each preparation of p...

example 2

Binding Assays

[0120]Binding assays are used to show protein-protein interactions, and can be used to determine which domains of proteins participate in the binding and to ascertain the relative binding affinity of various domains. Binding assays are also used to screen large numbers of peptides, such as those in a combinatorial library. It is particularly useful to screen peptides for the ability to bind to the NAT12 peptide or to the thrombin receptor. Peptides that show activity in one or more of the binding assays are also tested in one or more of the in vitro functional assays, such as those described in Example 1. A combination of binding and functional assays can be used to identify compounds that selectively inhibit thrombin-induced platelet and other cell activation.

A. Assay for Binding to the NAT12 Peptide

[0121]Peptides from a combinatorial library are linked to microtiter plates and the wells are blocked with 1% BSA. Biotinylated-NAT12 is incubated with the microtiter plat...

example 3

In Vivo Clearance and Function: Correlation With In Vitro Results

[0123]Clearance studies were performed in New Zealand white rabbits weighing between 2.0 and 2.5 kg. Rabbits were premedicated according to the method of Michelson et al., J. Mol. Cell Cardiol. 20, 547 (1988) with 10 mg / kg 1 M xylazine and 10 mg / kg 1 M ketamine. After tracheostomy, intubation, and positive pressure ventilation done with room air (Harvard instruments), stage III surgical anesthesia was maintained with 20 mg / ml of intravenous pentobarbital. A carotid artery and a jugular vein were then exposed. A catheter was inserted into the exposed carotid artery for withdrawal of blood samples and monitoring the animal's blood pressure (Gould, Inc., Cardiovascular Products, Oxnard. Calif.). In a similar manner, a catheter was inserted into the exposed jugular vein for administering the anesthetic and BK analog.

[0124]A single intravenous infusion of BK analog was injected. The amount of BK analog injected was calculat...

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PUM

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Abstract

The present invention provides bradykinin peptide analogs, compositions, and methods of inhibiting thrombin-induced platelet and other cell activation. The bradykinin analogs comprise single or multiple peptide segments. The invention also provides a method for identifying compounds that selectively inhibit thrombin-induced platelet and other cell activation.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. provisional application Ser, No. 60 / 046,085, filed Apr. 23, 1997.REFERENCE TO GOVERNMENT GRANT[0002]The invention described herein was made, in part, in the course of work supported by the National Heart Lung and Blood Institute under Grant Nos. HL35553, HL55907, HL52779, and HL56415. The government has certain rights in the invention.FIELD OF THE INVENTION[0003]This invention relates to the inhibition of thrombin-induced cell activation, and to the identification of compounds that inhibit thrombin-induced cell activation.BACKGROUND OF THE INVENTION[0004]Bradykinin is a vasoactive peptide released from the precursor plasma kininogens by kallikrein and other enzymes (Silva et al., Amer. J. Physiol. 156: 261-274 (1949)). Bradykinin has been described to have multiple physiologic functions, including the stimulation of prostacyclin production (Hong, S. L., Thromb. Res. 18, 787 (1980); Crutchley et ...

Claims

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Application Information

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IPC IPC(8): C07K5/09C07K7/00
CPCC07K5/0212C07K7/18C07K5/0817
Inventor SCHMAIER, ALVIN H.HASAN, AHMED A. K.
Owner MICHIGAN UNIV OF THE RGT
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